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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Manganese-induced neurotoxicity in cerebellar granule neurons due to perturbation of cell network pathways with potential implications for neurodegenerative disorders

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Author(s):
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Hernandez, Raul Bonne [1, 2, 3] ; Carrascal, Montserrat [4] ; Abian, Joaquin [4] ; Michalke, Bernhard [5] ; Farina, Marcelo [6] ; Gonzalez, Yasmilde Rodriguez [7] ; Iyirhiaro, Grace O. [7] ; Moteshareie, Houman [2] ; Burnside, Daniel [2] ; Golshani, Ashkan [2] ; Sunol, Cristina [3]
Total Authors: 11
Affiliation:
[1] Univ Fed Sao Paulo, Dept Exact & Earth Sci, Lab Bioinorgan & Environm Toxicol LABITA, Rua Prof Artur Riedel 275, BR-09972270 Diadema, SP - Brazil
[2] Carleton Univ, Dept Biol, 209 Nesbitt Biol Bldg, 1125 Colonel Dr, Ottawa, ON K1S 5B6 - Canada
[3] IDIBAPS, IIBB CSIC, Inst Invest Biomed Barcelona, Dept Neurochem & Neuropharmacol, Barcelona - Spain
[4] IDIBAPS, IIBB CSIC, Inst Invest Biomed Barcelona, CSIC UAB Prote Lab, Barcelona - Spain
[5] Helmholtz Zentrum Munchen GmbH, German Res Ctr Environm Hlth, Res Unit Analyt BioGeoChem, Ingolstadter Landstr 1, D-85764 Neuherberg - Germany
[6] Campus Univ Trindade, Ctr Ciencias Biol, Dept Bioquim, Campus Univ, Bloco C Univ Fed Santa Catarina, BR-88040900 Florianopolis, SC - Brazil
[7] Univ Ottawa, Fac Med, Dept Cellular & Mol Med, 451 Smyth Rd, Ottawa, ON K1H 8M5 - Canada
Total Affiliations: 7
Document type: Journal article
Source: METALLOMICS; v. 12, n. 11, p. 1656-1678, NOV 1 2020.
Web of Science Citations: 0
Abstract

Manganese (Mn) is essential for living organisms, playing an important role in nervous system function. Nevertheless, chronic and/or acute exposure to this metal, especially during early life stages, can lead to neurotoxicity and dementia by unclear mechanisms. Thus, based on previous works of our group with yeast and zebrafish, we hypothesized that the mechanisms mediating manganese-induced neurotoxicity can be associated with the alteration of protein metabolism. These mechanisms may also depend on the chemical speciation of manganese. Therefore, the current study aimed at investigating the mechanisms mediating the toxic effects of manganese in primary cultures of cerebellar granule neurons (CGNs). By exposing cultured CGNs to different chemical species of manganese ({[}{[}2-{[}(dithiocarboxy)amino]ethyl]carbamodithioato]](2-)-kS,kS `]manganese, named maneb (MB), and {[}{[}1,2-ethanediylbis{[}carbamodithioato]](2-)]manganese mixture with {[}{[}1,2-ethanediylbis{[}carbamodithioato]](2-)]zinc, named mancozeb (MZ), and manganese chloride (MnCl2)), and using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, we observed that both MB and MZ induced similar cytotoxicity (LC50 similar to 7-9 mu M), which was higher than that of MnCl2 (LC50 similar to 27 mu M). Subsequently, we applied systems biology approaches, including metallomics, proteomics, gene expression and bioinformatics, and revealed that independent of chemical speciation, for non-cytotoxic concentrations (0.3-3 mu M), Mn-induced neurotoxicity in CGNs is associated with metal dyshomeostasis and impaired protein metabolism. In this way, we verified that MB induced more post-translational alterations than MnCl2, which can be a plausible explanation for cytotoxic differences between both chemical species. The metabolism of proteins is one of the most energy consuming cellular processes and its impairment appears to be a key event of some cellular stress processes reported separately in other studies such as cell cycle arrest, energy impairment, cell signaling, excitotoxicity, immune response, potential protein accumulation and apoptosis. Interestingly, we verified that Mn-induced neurotoxicity shares pathways associated with the development of Alzheimer's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, and Parkinson's disease. This has been observed in baker's yeast and zebrafish suggesting that the mode of action of Mn may be evolutionarily conserved. (AU)

FAPESP's process: 16/50483-6 - Modeling in yeast the neurotoxicity and neurodegeneration induced by manganese
Grantee:Raúl Bonne Hernández
Support Opportunities: Regular Research Grants
FAPESP's process: 15/24207-9 - Development and application of an adverse outcome pathway framework for understanding and predicting neurotoxicity of development and manganese-induced neurodegeneration
Grantee:Raúl Bonne Hernández
Support Opportunities: Regular Research Grants
FAPESP's process: 16/00371-7 - Toxicogenomic cross-species studies to develop an adverse outcome pathway framework for understanding and predicting both neurotoxicity during development and manganese-induced neurodegeneration
Grantee:Raúl Bonne Hernández
Support Opportunities: Scholarships abroad - Research
FAPESP's process: 14/08990-2 - Proteomic and metallomic studies for understanding the developmental neurotoxicity induced by manganese-containing pesticides
Grantee:Raúl Bonne Hernández
Support Opportunities: Scholarships abroad - Research